tbuckley/cabot-search huggingface dataset:
Who coauthors Cochrane Reviews related to genitourinary cancers? A 1998-2022 analysis of country and gender diversity.
Authors: Sahaam Mirza, Ahmad Ozair, Abhishek Kumar, Nishanth R Subash, Moben Mirza
Journal: Journal of Clinical Oncology (2023)

436 Background: Women and individuals from low- and lower-middle-income countries (LMICs) are under-represented in urology literature, particularly in high-impact publications. Cochrane, a non-profit collaboration, publishes high‐quality systematic reviews that frequently impact policy and clinical practice worldwide. However, the state of the country and gender diversity amongst authors of urology-related Cochrane Reviews is unknown, which this work sought to determine. Methods: We searched the Cochrane Database, under the filter “Topic: Urology”, for all reviews related to genitourinary cancers, published until 25 July 2022, including both active reviews and those withdrawn for updation. We extracted authorship data and classified the national affiliation of authors into either high- and upper-middle-income countries (HICs) or LMICs based on the World Bank income classification. We treated a collaborative author group belonging to one country as a single-country affiliation. Given the higher accuracy of manual web searches for ascertaining gender over algorithmic estimation, we utilized the former to achieve ≥90% ascertainment. We endeavored to capture at least one webpage that demonstrated their gender, e.g. institutional profile, Google Scholar, ResearchGate, etc. Results: A total of 54 urology-related reviews, co-authored by a total of 324 authors, were included. 53 reviews were published by the Cochrane Urology Group, while one review was by the Incontinence Group. Zero authors were from LMICs. Countries with the highest representation of co-authors were the US (24.1%), UK (25.3%), Germany (23.5%), South Korea (6.8%), Australia (6.2%), Netherlands (3.7%), China (2.8%), Canada (2.5%), Brazil (1.5%). Gender could be ascertained for 94.14% (N=305/324) of co-authors. Women made up 27.5% (N=84/305) of co-authors, 16.0% (N=8/50) of first authors, and 16.89% (N=9/53) of corresponding authors. Conclusions: Women are well-represented in Cochrane Reviews related to genitourinary cancers compared to urology-specific journals and their representation in urology. However, LMICs contributed zero authors, while those from the US, UK, and Germany constitute &gt;70% of authors for one of the highest-quality evidence sources in urology. Equitable authorship representation may help expand both the utilization and the global relevance of recommendations of such high-impact urology literature. Global capacity-building efforts are warranted, particularly in Africa, for enhancing the involvement of LMIC urologists with evidence synthesis.
A phase II study of risk-based stratification after chemotherapy combined with PD-1 antibody: Two various bladder-sparing modalities for muscle invasive bladder cancer therapy (ReBirth).
Authors: Yijun Shen, Xiaolin Lu, Xuejun Ma, Wei Liu, Dingwei Ye
Journal: Journal of Clinical Oncology (2023)

TPS580 Background: Neoadjuvant chemotherapy plus radical cystectomy is the standard for cisplatin-eligible patients with cT2-4aN0M0 muscle invasive bladder cancer, however, some of them desperately need innate bladder. Developments in the last two decades suggest that well-documented Trimodal therapy(TMT) demonstrated durable oncologic control and long-term survival in selected patients. Nevertheless, personalized treatment based on responses of systematic treatment and biomarker are currently lacking. Additionally, concerning a balance between non-inferiority of hypofractionated radiation therapy in local control and late toxicity, the specified dose regimen combined with immunotherapy is worth exploring. "ReBirth" study was designed to evaluate the efficacy and tolerability of two various bladder-sparing modalities with risk-based stratification after chemotherapy combined with PD-1 antibody. Methods: This is a single-arm, phase II trial that includes cT2-4aN0-1M0 patients who aged 18-85 years and histologically confirmed bladder urothelial carcinoma. Other key inclusion criteria: no prior anti PD-(L)1 therapy; ECOG 0-2 and cisplatin eligible. The trial consists of two stages. In the first stage, eligible patients will receive tislelizumab 200 mg in day 1 (D1), cisplatin 70 mg/m 2 D1, and gemcitabine 1000 mg/m 2 D1 and D8 every 21 days for four cycles. Patients will then be divided into two cohorts in the second stage based on the cystoscopy, urine cytology, and imaging combined with utDNA (urine tumor DNA). Patients who achieve clinical complete response (cT0, cTa) will enter into cohort 1 and treated with tislelizumab 200 mg IV Q3 for up to 6 months, while patients who did not achieve clinical complete response will enter into cohort 2 and treated with tislelizumab 200 mg IV Q3W for up to 6 months and chemoradiotherapy for whole bladder 44Gy/16 fractionation, if lymph node is positive, it can be dosed to the maximum tolerable dose, such as tumor boost 11Gy/4fractionation, combined with DDP as radiosensitizer. The primary endpoint is BIDFS (bladder intact disease-free survival) at one year, which is defined as time from initiation of protocol therapy until the development of muscle-invasive bladder cancer recurrence, regional pelvic recurrence, distant metastases, bladder cancer-related death, or cystectomy. Secondary endpoints include metastatic free survival rate at two years, BIDFS at two years and safety graded according to CTCAE V5.0. Tissue samples will be collected for genomic profiling and utDNA will be collected and examined for biomarker exploring in this bladder preservation therapy. Till Sep.2022, 5 of planned 30 patients have been enrolled. Clinical trial information: NCT05531123 .
Biomarkers of response to enfortumab vedotin (EV) in patients (pts) with advanced urothelial carcinoma (aUC): Analysis of the UNITE study.
Authors: Tanya Jindal, Deepak Kilari, Omar Alhalabi, Amanda Nizam, Ali Raza Khaki, Arnab Basu, Pedro C. Barata, Mehmet Asim Bilen, Sumit Shah, Yousef Zakharia, Matthew I. Milowsky, Joaquim Bellmunt, Hamid Emamekhoo, Nancy B. Davis, Petros Grivas, Shilpa Gupta, Christopher J. Hoimes, Matthew T Campbell, Ajjai Shivaram Alva, Vadim S Koshkin
Journal: Journal of Clinical Oncology (2023)

450 Background: EV, an antibody-drug conjugate (ADC) targeting Nectin-4, is used widely in treatment-refractory aUC, but limited data are available on biomarkers predictive of EV outcomes. We investigated potential biomarkers of response to EV in a pt cohort in the UNITE dataset. Methods: We included the retrospective UNITE study pts from 16 sites, with available next generation sequencing using institutional or commercial platforms, treated with EV alone outside clinical trials. Observed response (ORR) was determined by investigators for evaluable pts with scans after ≥1 dose of EV. Assessed molecular biomarkers included tumor mutation burden (TMB), PD-L1 status, somatic alterations (alts) in ≥ 10% of pts ( TERTp, TP53, ARID1A, CDKN2A, CDKN2B, FGFR3, ERBB2, CCND1, KDM6A, MTAP, PIK3CA, RB1, TSC1) and presence of ≥1 DNA damage response mutations ( ATM, BARD1, BRCA1, BRCA2, CDK12, CHEK2, PALB2, PPP2R2A, or RAD51B). ORRs were compared using Chi-squared test, while median progression-free and overall survival (mPFS, mOS) from EV start were compared with log-rank test and Cox proportional hazards in pts with and without biomarker presence. Results: A total of 170 pts had outcomes and NGS data available. Median age was 70, 133 (78%) were men, 144 (85%) Caucasian, 110 (65%) with pure urothelial histology, 118 (69%) with primary bladder tumor, and 116 (68%) had ≥ 2 lines of therapy before EV. For all pts, ORR 47%, mPFS 6 mos, mOS 12 mos. ORRs were higher in pts with ERBB2 (67% vs 44%; p = 0.05) and TSC1 (68% vs 25%; p=0.04) alts vs wild-type. Shorter mPFS was noted in pts with CDKN2A, CDKN2B, and MTAP alts, and longer mOS in pts with high TMB (table). Conclusions: This large, multi-site, retrospective cohort of pts with aUC identified several potential biomarkers associated with differential outcomes to EV. These findings, upon external validation, may help inform clinical decision making and potential therapy sequencing with available ADCs. Limitations include retrospective nature, pt selection, and confounding biases. [Table: see text]
Risk analysis of open vs. robotic assisted radical cystectomy.
Authors: Rishabh Kumar Simhal, Kerith Ruoyao Wang, Yash Shah, Daniel P Simon, James Ryan Mark, Mihir S Shah, Leonard G. Gomella, Thenappan Chandrasekar, Costas D. Lallas
Journal: Journal of Clinical Oncology (2023)

576 Background: Radical cystectomy (RC) is standard of care for muscle-invasive bladder cancer, but it comes with significant perioperative risk with half of patients experiencing major postoperative complications. Robot-assisted radical cystectomies (RARC) have aimed to decrease patient morbidity and have become increasingly adopted in North America. Currently, both open radical cystectomies (ORC) and RARC are frequently performed. To contribute to the existing literature using newly available data from the American College of Surgeons National Surgical Quality Improvement Project (NSQIP), representing one of the most recent, largest multi-institutional studies, while uniquely accounting for a variety of factors including type of urinary diversion, cancer staging, and neoadjuvant chemotherapy. Methods: RC procedures performed between 2019-2020 were identified in NSQIP and the corresponding Cystectomy Targeted database. Cases in the ORC group were planned open procedures, and cases in the RARC group were robotic with intra- or extracorporeal diversions, including unplanned conversion to open cases for intention-to-treat. Chi-square and t-tests were performed to compare baseline demographics and operative parameters. Multivariate analysis was performed for outcomes including major complications, minor complications, and 30-day mortality, while adjusting for operative approach, medical comorbidities, functional status, age, race, sex, BMI, ASA-classification, preoperative labs, type of urinary diversion, pathological staging, prior pelvic surgery or radiation, need for preoperative transfusion, preoperative sepsis, emergent or elective surgery, and recent chemotherapy. Results: 4,022 RC cases were identified. Of these, 3,146 (78.2%) received planned ORC while 876 (21.8%) received RARC. Baseline demographics of the patients who received ORC versus RARC were largely similar, with no significant difference in age or medical comorbidities. RARC was associated with longer operative times and shorter hospital length of stay compared to ORC. On multivariate analysis, ORC was associated with a higher rate of 30-day mortality [OR 3.1; 95% CI 1.3-7.2; p=0.009], reintubation, cardiac arrest, superficial wound infection, bleeding requiring transfusion [OR 4.7; 95%CI 3.6 - 6.1; p&lt;0.001], prolonged postoperative nasogastric tube use, rectal injury, and ureteral fistula or urine leak compared to RARC. Conclusions: In the NSQIP database, ORC is associated with higher rates of 30-day mortality and operative complications, most notably bleeding, compared to RARC. This study is unique in the size of the cohorts compared, the timeliness of the data (2019-2020), and the ability to control for factors, such as type of urinary diversion, pathological bladder cancer staging, and use of neoadjuvant chemotherapy.
Characterization and survival benefit of drugs approved for advanced renal cell carcinoma.
Authors: David Joseph Benjamin, Arash Rezazadeh
Journal: Journal of Clinical Oncology (2023)

633 Background: The treatment landscape of advanced renal cell carcinoma (RCC) drastically changed with the approval of tyrosine kinase inhibitors (TKIs). Since then, immunotherapy (IO) and now TKI plus IO combination therapies is considered standard-of-care. Despite multiple drug approvals, it remains unclear how much improvement in survival these therapies have provided. Methods: We reviewed the US Food and Drug Administration (FDA) website to evaluate all approvals for RCC from 2005 to 2022. We collected progression-free survival (PFS) and overall survival (OS) from the approval notification or from the corresponding clinical trial cited for drug approval. Results: Between 2005 and 2022, there were 16 drug (single or combination) approvals for advanced RCC. Most therapy approvals (93.75%) were granted through accelerated approval. Eight approvals were TKIs, 6 approvals were TKI plus IO combination therapies, and 1 approval each were for immunotherapy and a VEGF inhibitor. Average PFS benefit for 1 st line approvals was 5.63 months (range 1.9-14.7) and average PFS benefit for 2 nd or later line approvals was 2.95 months (range 0.2-9.1). Average OS benefit in the 1 st line setting was 3.6 months and average OS benefit in the 2 nd or later line setting was 5.4 months. Conclusions: Despite 16 drug (single or combination) approvals for advanced RCC since 2005, the improvements in average PFS and OS were modest. As OS data matures from recent TKI plus IO combination therapies, OS benefit may improve. Nonetheless, continued drug development is urgently warranted in advanced RCC. [Table: see text]
Persistent need for systematic biopsy for those on active surveillance for early-stage prostate cancer.
Authors: Mary Fakunle, Janet E. Cowan, Samuel L. Washington, Hao G Nguyen, Matthew R. Cooperberg, Peter Carroll
Journal: Journal of Clinical Oncology (2023)

322 Background: Serial biopsy is a mainstay of surveillance for patients on active surveillance for prostate cancer. mpMRI targeting has become a standard for targeting lesions during biopsy as it allows for better identification of the dominant lesion (grade and/or volume). It is unclear whether “targeted biopsy” alone reliably identifies the dominant lesion on serial biopsy, thereby obviating the need for systematic biopsy. The aim of this study was to assess whether targeting alone can consistently identify the dominant lesion on serial biopsies for active surveillance. Methods: Participants enrolled in active surveillance with early-stage prostate cancer (PSA &lt;20, cT1-2, GG1 and 2) at diagnosis and underwent two or more MR fusion biopsy sessions that include both systematic and targeted sampling. Timing and frequency of Gleason upgrading were assessed. Grade and sextant location within the prostate were compared between the systematic and targeted cores to determine concordance. Results: Of 619 men who had multiple MR targeted biopsies, 80% were GG 1 at time of diagnosis and 20% were GG 2. Fifteen percent had their first MR fusion biopsy as their diagnostic, 41% on confirmatory biopsy, and 44% on subsequent surveillance biopsy. The highest grade was sampled by MR targeting from 70% to 91% of the time. In a subset of 106 men with GG1 at first MR fusion biopsy and a subsequent MR fusion biopsy within 36 months, Gleason upgrading was detected in 47 men (44%) on the 2 nd MR fusion biopsy. When comparing upgrading between systematic and MRI targeting, 20 men (42%) upgraded inside the target only. Twenty-one men (45%) upgraded on both systematic and MR targeted biopsy. And 6 men (13%) upgraded on systematic biopsy only. Conclusions: In those with serial MR-targeted biopsies, targeting alone identified a majority of upgrading. However, it missed a portion of with upgrading outside the target. This suggests that those on active surveillance, with MR targets, still benefit from systematic biopsies.
Circulating tumor DNA analysis of IMbassador250: Association of ctDNA fraction, AR alterations and therapy outcome in mCRPC.
Authors: Christopher Sweeney, Ryon Graf, David Fabrizio, Kobe Yuen, Matthew J. Wongchenko, Pratyush Gupta, Priti Hegde, Geoffrey R. Oxnard, Thomas Powles
Journal: Journal of Clinical Oncology (2023)

LBA249 Background: IMbassador250 was a prospective phase III international trial which showed no overall survival (OS) benefit for adding atezolizumab to enzalutamide for men with mCRPC who had prior progression on abiraterone. We hypothesized that genomic biomarkers in ctDNA may identify patients who have poorer OS with 2 nd generation novel hormonal therapy. Methods: Pre-treatment (but post-abiraterone progression) plasma samples from IMbassador250 were submitted for comprehensive genomic profiling using FoundationOne Liquid CDx. We detected elevated ctDNA tumor fraction (TF) using a novel algorithm that incorporates aneuploidy as well as tumor-derived short variant signal. A pre-specified TF cutoff of ≥ 2% was defined as high. A prospective-retrospective biomarker statistical analysis plan was developed in accordance with Simon Criteria, pre-specifying analyses, cutoffs, and power assessments. Results: 494 baseline plasma specimens were evaluable. The TF high group [371 (74%)] had significantly shorter OS than TF low (median 11.0 vs. 22.1 months, HR 4.3, 95% CI 3.0 – 6.1, p &lt; 0.0001) (primary endpoint). Pre-specified supportive analyses compared the performance to prognosticate OS (concordance [std error]) of baseline PSA alone (0.65 [0.63 – 0.67]) to a model consisting of all evaluable baseline features including PSA, treatment arm, age, race, ECOG score, hemoglobin, alkaline phosphatase, albumin, number of metastatic sites, and sites of metastasis (0.71 [0.70 – 0.73]) to TF alone (0.72 [0.71 – 0.73]) to all features plus TF (0.76 [0.74 – 0.77]). Likelihood ratio test for improvement of OS prediction by adding TF to all available clinical features: p &lt; 0.0001. Focusing on the patients with TF ≥ 2% (n = 371) exploratory analysis observed less favorable outcomes with detection of AR amplifications (n = 203 [55%], HR: 1.4, 95%CI: 1.1 – 1.8), while individual AR mutations were not as strongly associated with OS: L702 ([16%], HR: 1.2, 95%CI: 0.88 – 1.7), W742 ([4.3%], HR: 0.59, 95%CI: 0.30 – 1.2), H875 ([9.4%], HR: 0.71, 95%CI: 0.46 – 1.1), T878 ([25.3%], HR: 0.86, 95%CI: 0.65 – 1.1). Conclusions: In this cohort TF &lt; 2% at baseline is strongly associated with favorable OS on enzalutamide after progression on abiraterone compared to TF ≥ 2%. TF alone has comparable discriminatory ability to anticipate overall survival compared to all available clinical features combined, and adds significant prognostic power when combined with clinical features in this setting. AR amplifications, but not mutations, further improve strengths of association. Clinical trial information: NCT03016312 .
Characterization and survival benefit of drugs approved for metastatic prostate cancer.
Authors: David Joseph Benjamin, Arash Rezazadeh
Journal: Journal of Clinical Oncology (2023)

81 Background: The treatment landscape of metastatic prostate cancer (mPC) drastically changed with the approval of chemotherapy (docetaxel) in 2004, and novel hormonal therapy (NHT) abiraterone in 2011. Since then, several other therapies have been approved in the metastatic castrate-sensitive (mCSPC) and -resistant (mCRPC) settings. Despite multiple drug approvals, it remains unclear how much improvement in survival these therapies have provided. Methods: We reviewed the US Food and Drug Administration (FDA) website to evaluate all approvals for prostate cancer from 2004 to 2022. We collected progression-free survival (PFS) and overall survival (OS) from the approval notification or from the corresponding clinical trial cited for drug approval. Results: Between 2004 and 2022, there were 14 drug (single or combination) approvals for mPC. Most approvals (81.3%) were granted through regular approval. Average PFS benefit for mCSPC was 4.8 months and average OS benefit for mCSPC was not reached in ongoing trials. Average PFS benefit for mCRPC was 3.7 months (range 1.9-5.4) and average OS benefit for mCRPC was 3.67 months. Conclusions: Despite 14 drug (single or combination) approvals for mPC since 2004, the improvements in average PFS and OS were modest in both castrate-sensitive and -resistant settings. OS data for several NHTs continues to mature, and may alter average OS benefits once median OS is reached. Nonetheless, continued drug development for mPC is warranted. [Table: see text]
Barriers to guideline-concordant use of bone modifying agents for prostate cancer.
Authors: Aaron Philip Mitchell, Sonia Persaud, Susan Chimonas, Andrew L. Salner, Paul Palyca, Azeez Farooki, Jamie S. Ostroff, Michael J. Morris
Journal: Journal of Clinical Oncology (2023)

68 Background: NCCN Guidelines recommend the use of bone-modifying agents (BMAs) to prevent skeletal-related events (SRE) for patients with castrate-resistant prostate cancer (CRPC) and bone metastasis, but not for castrate-sensitive prostate cancer (CSPC). Prior studies have identified both underuse of BMAs for CRPC and overuse for CSPC, but the clinical circumstances underlying these apparent gaps in care are unknown. Methods: Qualitative interview study, with physicians who treat prostate cancer within an academic cancer center and an affiliated network of community-based practices. Using a semi-structured interview guide, an experienced moderator probed participants’ experiences and perceptions around NCCN Guidelines recommendations, guideline adherence and non-adherence, and barriers to adherence. Interviews also probed participants’ views of potential interventions to promote guideline-concordant BMA use. Participants used Likert-scale items to rate the likely effectiveness of each intervention in influencing BMA practice patterns. They also identified the 3 most helpful interventions for reducing BMA underuse and overuse separately. Results: 19 physicians were invited, of whom 15 agreed to participate; 1 physician did not respond to some questions as outside scope of practice. All were aware of the recommendation for use of BMAs in CRPC. 14% (2/14) were unaware of the recommendation against BMA use for CSPC; an additional 29% (4/14) believed that BMA use could be appropriate for CSPC depending on the burden of bony metastatic disease. 36% (5/14) were unaware of recommendations for baseline DEXA scan and BMA for patients with low bone mineral density. The most commonly reported barriers (occurring “often” or “sometimes”) to BMA use for CRPC were obtaining dental clearance (11/15) and insufficient time in clinic (6/15). The interventions perceived as most helpful to reduce underuse for CRPC were dental navigation (11/15) and EMR-based guidance (9/15). The interventions identified as most helpful to reduce overuse for CSPC were peer-to-peer education (14/15) and EMR-based guidance (13/15). Conclusions: Among physicians treating prostate cancer in our study, there was incomplete awareness of guideline recommendations for screening and treatment of low bone mineral density, and against BMA use for SRE prevention in CSPC. Dental navigation, peer-to-peer education, and EMR-based guidance were preferred implementation strategies to reduce underuse and overuse of BMAs.